Everything You Ever Wanted to Know About Transplant But Were Afraid to Ask

1. Everything You Ever Wanted to Know About Transplant But Were Afraid to Ask Jeffrey Schriber, M.D. FRCP (c) Medical Director Cancer Transplant Institute Virginia G. Piper Cancer Center

2. Suddenly, Dr. Schriber realized he had left his brain in Toronto

3. Objectives • Understand Basic Principles of Transplantation • Understand Differences between Autologous and Allogeneic Transplants • Understand which Diseases are best treated by each type of Transplant • Understand Major Complications of each type of Transplant

4. Stem Cell Transplant Principles • Dose Intensity • Stem Cell Rescue • Immune System

7. Dose Intensity • Active Agents at Conventional Doses • Avoid Overlapping Nonhematologic Toxicity • Non Cross Resistant Agents • Immunosuppressive* *Allo only

8. Dose Intensity • Increase dose intensity of Cytotoxic Chemotherapy • Up to 10-fold over conventional therapy • Up to 2.5 times MTD without stem cell support • TBI • Busulfan • ThioTEPA

9. Dose Limiting Toxicities • BCNU • Busulfan • Carboplatinum • Cyclophosphamide • Etoposide • Thiotepa • Pulmonary • Gastrointestinal • Renal • Cardiac • Mucosal • CNS

10. Stem Cell Properties • Capable of Producing all Blood cell lines • Capable of Self Renewal • Rare in Resting Peripheral Blood • Has Marker called CD 34

12. Steps in Stem Cell Transplant • Prior therapy to decrease tumor burden • Disease and Functional Testing • Choose Donor (auto vs. allo) • Transplant Regimen • Cytoreductive • Immunosuppressive • Period of Neutropenia • Count Recovery

13. Autologous Stem Cell Transplant • “Trick” to give high doses of chemotherapy • Use Stem Cells to Recover • Cytopenic Phase (Need for transfusions, antibiotics, pain control) • Late Complications Rare • Most Common Cancer Treated is Myeloma

14. HSCT: Choice of Stem Cells: Autologous • Advantages • Available for most patients • No graft vs. host disease • Regimen can be optimized for antitumor activity • Low morbidity & mortality • Few long-term complications

15. HSCT: Choice of Stem Cells: Autologous • Disadvantages • Contamination with tumor • Stem cell damage from prior cytotoxic therapy • No graft vs. tumor reaction

16. Changes in Autologous Transplant: Myeloma

17. Multiple Myeloma Outcomes 0 % Mortality

18. Allogeneic Stem Cell Transplant • True Transplant of the Immune System • Need to Find a Donor • Sibling • Unrelated • Cord Blood • Cytopenic Phase • Immunosuppressive therapy early and late

19. HSCT: Choice of Stem Cells: Allogeneic • Advantages • No contamination with tumor • Graft vs. tumor reaction • No exposure to prior therapy

21. HSCT: Choice of Stem Cells: Allogeneic • Disadvantages • Lack of compatible donors • Graft vs. Host Disease • Prolonged immunosuppression necessary • Higher morbidity & mortality

22. HSCT: Complications • Toxicity of Preparative Regimen • Mucosal, Liver, Lung, (Heart) • Myelosuppression, Immunosuppression • Infection, Hemorrhage • Graft vs. Host Disease (allo only) • Acute 80% (20-40% severe) • Chronic 30% • Overall Mortality • Allogeneic: 10-40% • Autologous: 1-5%

24. Acute GVHD • Typically first 100 days • Skin • Rash (from minimal to desquamation) • Liver • Hyperbilirunemia, Elevated ALP • Gut • Diarrhea • Persistent Nausea

25. GVHD of the SkinRecurrence of GVHD

26. Chronic GVHD • Later appearing • More like autoimmune disease • Skin • Mucous membranes • Mouth • Eyes • Vagina • Lung, Liver, Joint Involvement • Bronchilitis

29. Prevention of GVHD • Remove T Cells • Eliminates GVHD • High Relapse Rate with lose of GVL • Add Backs at later date • Selective Removal of T subsets • Remains under investigation

30. Prevention of GVHD • Calcineurin inhibitors (Cyclosporine and Prograf) • Inhibit Ca+ dependent signaling protein for IL 2 transcription (via TCR) • Rapamycin • Inhibits protein kinase required for protein synthesis and cell cycle progression (cytokines and growth factors) • MMF • Inhibits enzyme responsible fro Nucleotide synthesizes in B and T lymphocytes

31. Prevention of GVHD • Prednisone • ATG • Rituxan • Methotrexate • Cyclophosphamide post Transplant • Antibodies to IL2, TNF

32. Autologous vs. Allogeneic Transplant • Donors Easily Available • Regimen Tailored • Potential Tumor Contamination • Low Morbidity / Mortality • No GVHD/GVT • Few Long Term Complications • Major Risk Relapse • Must Find Donor • Regimen must be Immunosuppressive • Higher Morbidity/ Mortality • GVHD both Acute and Chronic as Major Complication • GVT Effect • Lower Risk of Relapse

33. Diseases Commonly Treated with Transplant • Acute Myeloid Leukemia • Acute Lymphoid Leukemia • Chronic Leukemia (CML, CLL) • Myelodysplastic Disorders • Congenital Disorders • Non Hodgkin’s Lymphoma (low or high grade) • Hodgkin’s Disease • Myeloma • Germ Cell

34. Nonmyeloablative Transplant • Less intense chemotherapy • Older patients now feasible • Decreased mucositis • Shift to outpatient therapy • Less transfusion requirements • No change in Chronic GVHD/GVL

35. Nonmyeloablative Transplant • Increase Patient Eligibility • Age to 70 • Allows for Cardiac Pulmonary function Hepatic Renal • Infection not absolute contraindication

36. Changes in Allogeneic Transplant: